The present invention is directed to sustained-release derivatives of hydroxylated analogs of substituted 1-[2[bis(aryl)methoxy]ethyl]-piperazines and -homopiperazines and their use.
Drug abuse is a major public health problem. One of the major drugs of abuse in the U.S. is cocaine. Cocaine is a locomotor stimulant, which acts as a local anesthetic and which inhibits the reuptake of norepinephrine, dopamine and serotonin, presumably by binding to a component of the macromolecular transporter complex that translocates biogenic amines from the synaptic space into the cytosol of the nerve terminus (Galloway, Trends Pharmacol. Sci. 8: 451-454 (1988)). The inhibition of norepinephrine reuptake results in sympathomimetic effects. The euphoric and addictive effects of cocaine, however, appear to result primarily from inhibition of mesolimbic dopamine reuptake (Ritz et al., Science 237: 1219-1223 (1987); Baumann et al., J. Pharmacol. Exper. Ther. 271(3): 1216-1222 (1994)).
Other evidence indicates that mesolimbic dopamine is a crucial neurochemical mediator of rewarding behaviors, e.g., eating and sex (Wise, xe2x80x9cBrain dopamine and reward,xe2x80x9d In Theory in Psychopharmacology, pp. 103-122, Cooper, ed., Academic Press (1981)). In vivo microdialysis studies have demonstrated that the level of extracellular dopamine increases in the nucleus accumbens of animals engaged in rewarding behavior, such as eating (Hernandez et al., Life Sci. 42: 1705-1712 (1988)) or cocaine self-administration (Hurd et al., Neurosci. Lett. 109: 227-233 (1990)). It is believed that the ability of a drug to elevate the level of mesolimbic extracellular dopamine is critical to its abuse (Di Chiara et al., PNAS USA 85: 5274-5278 (1988)) and those drugs that inhibit dopamine reuptake, thereby resulting in addictive and euphorogenic effects, are classified as xe2x80x9ctype 1 blockersxe2x80x9d (Rothman, Life Sci. 46: PL-17-PL-21 (1990)).
Increased use of cocaine in the 1980""s (Adams et al., xe2x80x9cCocaine: A growing public health problemxe2x80x9d In Cocaine: Pharmacology, Effects and Treatment of Abuse, NIDA Research Monograph 50, Grabowski, ed., U.S. Gov""t Printing Office, Washington, D.C. (1984); and Kozel et al., Science 34: 970-974 (1986)) resulted in a parallel increase in cocaine use by opioid-dependent and methadone-maintained patients (Kosten et al., Am. J. Drug Alcohol Abuse 12: 1-16(1986); J. Clin. Psychiatry 48-442-444 (1987); Cushman, Hosp. Community Psychiatry 39: 1205-1207 (1988); and Condelli et al., J. Subst. Abuse Treat. 8: 203-212 (1991)). The increase in use of cocaine has been further compounded by the link between intravenous drug abuse and the spread of HIV. Consequently, public awareness of drug abuse has increased, leading to drug abuse treatment becoming a national priority in the U.S. Accordingly, there is a constant and ever growing need for pharmacotherapies, which enable the treatment of larger numbers of drug abusers than would otherwise be possible with nonpharmacological treatment modalities and which can be coupled with more traditional treatment approaches, such as counseling and rehabilitation.
One pharmacotherapeutic approach is to develop a competitive cocaine antagonist, i.e., a drug that will bind to the dopamine transporter but will not inhibit dopamine reuptake (Rothman et al., Pharma. Biochem. and Behav. 40: 387-397 (1991)). Such a cocaine antagonist would be expected to block cocaine from increasing the level of extracellular dopamine. However, a patient could overcome the inhibitory effect of a competitive cocaine antagonist by self-administering more cocaine.
Another pharmacotherapeutic approach is to develop a noncompetitive cocaine antagonist. The noncompetitive cocaine antagonist would be one that binds to the dopamine transporter with high affinity and dissociates slowly. The noncompetitive cocaine antagonist would then provide a sustained increase in the level of extracellular dopamine, thereby providing the drug abuser with some relief from cocaine-craving due to dopamine deficiency, yet inhibiting cocaine from further elevating the level of extracellular dopamine and increasing the probability of increased toxic side effects.
One such noncompetitive cocaine antagonist is the compound 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine, otherwise known as vanoxerine or GBR 12909 (Rothman et al. (1991), supra; and Rothman et al., WO 91/01732). Vanoxerine is a selective inhibitor of dopamine reuptake and is about 700-fold more potent than cocaine in inhibiting dopamine reuptake in vitro (Andersen, Eur. J. Pharmacol. 166: 493-504 (1989)). Unlike cocaine, however, vanoxerine-inhibited dopamine reuptake does not result in addictive and euphorogenic effects and, thus, vanoxerine is considered to be a xe2x80x9ctype-II blockerxe2x80x9d (Rothman (1990), supra). In addition, although cocaine and vanoxerine produce equivalent motor-stimulating effects, vanoxerine must occupy the dopamine transporter to a greater extent than cocaine in order to produce equivalent behavioral effects (Rothman et al., Pharmacol. Biochem. and Behav. 43: 1135-1142 (1992)). Similarly, although cocaine and vanoxerine cause dose-related elevations in extracellular dopamine when given alone, cocaine causes a rapid and short-lived increase in dopamine, whereas vanoxerine causes a low and sustained elevation of dopamine (Baumann et al. (1994), supra).
Recently, the ability of vanoxerine to inhibit xe2x80x9ccocaine-maintained respondingxe2x80x9d without inhibiting xe2x80x9cfood-maintained respondingxe2x80x9d was demonstrated in rhesus monkeys (Macaca mulatta) (Glowa et al., Exper. and Clin. Psychopharmacology 3(3): 219-231 (1995a)). Subsequent studies showed that repeated treatments of rhesus monkeys with lower doses of vanoxerine could sustain these behaviorally-selective effects (Glowa et al., Exper. and Clin. Psychopharmacology 3(3): 232-239 (1995b)).
Another cocaine antagonist is 1-[2-(diphenyl-methoxy)-ethyl]-4-(3-phenylpropyl)homopiperazine, otherwise known as LR1111, which is a homolog of 1-[2-diphenyl-methoxy-ethyl]-4-(3-phenylpropyl)piperazine, otherwise known as GBR12935 (Rothman et al., Synapse 14: 34-39 (1993)). LR1111, which differs from GBR12935 by the addition of a methylene group to the piperazine ring, has affinity for the dopamine transporter similar to that of GBR12935 but with significantly higher selectivity (Rothman et al. (1993), supra). In addition, LR1111 is over 4,000-fold more selective for the dopamine transporter than the serotonin and norepinephrine transporters (Rothman et al. (1993), supra).
Other structurally related dopamine reuptake inhibitors are also known. See, for example, van der Zee et al., Eur. J. Med. Chem.xe2x80x94Chimica Therapeutica 15(4): 363-370 (1980); van der Zee et al., Neuropharmacology 24(12): 1171-1174 (1985); Gootjes et al., EP 0 099 148 (published Jan. 25, 1984); Gootjes et al., U.S. Pat. No. 4,476,129 (issued Oct. 9, 1984); and Matecka et al., Med. Chem. Res. 5: 43-53 (1994).
Unfortunately, some of the above compounds are not suitable for use as pharmacotherapeutic agents because they are not limited in their effect. For example, some of the above compounds have been shown to inhibit both xe2x80x9ccocaine-maintained respondingxe2x80x9d and xe2x80x9cfood-maintained respondingxe2x80x9d in monkeys (Glowa et al. (1995b), supra).
Other of the above compounds, although they are limited in effect, are not long-lasting in effect. In other words, use of such compounds requires frequent and regular dosing. Such a characteristic is undesirable for a pharmacotherapeutic agent to be used in the treatment of drug abuse, such as, for example, cocaine abuse, where patient noncompliance is a major issue affecting success of treatment.
In view of the above, there remains a need for a dopamine reuptake inhibitor that binds the dopamine transporter with high affinity, selectivity and specificity and that is long-lasting in effect, such that dosing frequency can be reduced, thereby reducing the potential impact of patient noncompliance on success of treatment. It is an object of the present invention to provide such a compound. In addition, it is an object of the present invention to provide a pharmaceutical composition comprising such a compound. Furthermore, it is an object of the present invention to provide a method of using such a compound to antagonize the effects, e.g., addictive and euphoric effects, of a dopamine reuptake inhibitor, e.g., cocaine, and a norepinephrine and/or serotonin reuptake inhibitor, e.g., methamphetamine. These and other objects and advantages of the present invention will become apparent from the description set forth below.
The present invention provides sustained-release derivatives of hydroxylated analogs of substituted 1-[2[bis(aryl)methoxy]ethyl]-piperazines and -homopiperazines. The hydroxylated analogs of substituted 1-[2-bis(aryl)methoxy]ethyl]-piperazines and -homopiperazines are derivatized for sustained-release by esterification of the hydroxyl group. Preferably, the hydroxyl group is esterified with a medium- to long-chain alkanoic acid. Preferably, the alkanoic acid comprises a C6-20 alkyl, C6-20 aryl alkyl, or a C6-20 cycloalkyl alkyl group. Examples of preferred alkanoic acids include decanoic acid, cyclopentyl propionic acid, phenyl propionic acid, valeric acid, caproic acid, heptanoic acid, and caprylic acid. A preferred substituted piperazine for hydroxylation and subsequent esterification in accordance with the present invention is 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine. A preferred sustained-release derivative of such a compound is the decanoate ester referred to herein as DBL 583 or, in the alternative, compound 5*, scheme 1, page 53, know as (+/xe2x88x92) 1-[2-[bis-(4-fluoro-phenyl)methoxy]ethyl]-4-[3-phenyl-3-hydroxy-propyl]piperazine. Preferably, the sustained release derivative has a pharmacological half-life of at least about 30 days.
Also provided by the present invention is a pharmaceutical composition comprising such a sustained-release derivative and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition is suitable for depot injection into, for example, the buttocks or thigh, such that a continuous release of a small portion of the derivative is continuously released, preferably over at least about 30 days, into the plasma until depleted.
The present invention further provides a method of using such a sustained-release derivative to bind the dopamine transporter as, for example, a noncompetitive antagonist of a dopamine reuptake inhibitor or an antagonist of a dopamine releaser or a norepinephrine and/or serotonin reuptake inhibitor, although the method is useful for other purposes where binding of the dopamine transporter by a present inventive compound has a desired effect. In accordance with the method, the sustained-release derivative is administered to an individual in need of such a compound. The sustained-release derivative is administered in a sufficient amount such that a desired effect is realized. For example, a dopamine reuptake inhibitor or a dopamine releaser or norepinephrine and/or serotonin reuptake inhibitor in the individual is antagonized over a period of time by a sustained release of the derivative during that period of time. Preferably, the compound is administered by depot injection. More preferably, the compound is administered by depot injection into the buttocks or thigh. Preferably, the period of time of antagonism is at least about 30 days. The method is especially useful in the treatment of an individual who abuses cocaine. To the extent that a sustained-release derivative in accordance with the present invention antagonizes a dopamine releaser or an inhibitor of norepinephrine and/or serotonin reuptake, such a derivative, a pharmaceutical composition comprising such a derivative, and a method of administering such a derivative are useful in the treatment of an individual who abuses amphetamines, such as methamphetamine, and phencyclidine.